There are many drug substances that exhibit undesirable changes when exposed to a moist environment, prior to administration. Depending on the particular drug, the changes can result from internal molecular changes such as hydrolysis, or from reactions with other components of the drug product formulation or with the atmosphere. Since drug product manufacturing cannot always be conducted in an environment having a low humidity, there can be significant drug degradation during the various production operations, prior to packaging a product. After packaging, stability of the products can be affected by moisture transfer through packaging components, as well as reactions involving components of the package atmosphere. Also, repeatedly opening and closing a package during normal use can expose the contents to atmospheric moisture. Due to normal fluctuations in the moisture content of the atmosphere, undesired changes that will be experienced with a moisture-sensitive drug are not predictable.
A frequent result of contact between a sensitive drug compound and moisture is a reaction that results in formation of one or more different chemical species. This can be simply a hydration of the drug molecule that results in different dissolution or other physical properties, or it can involve a reaction that produces a different compound having a diminished intended pharmacological activity. In some instances, a new molecular entity that is produced can have a radically different pharmacological activity that is harmful when administered.
Regulatory agencies require demonstration of drug stability, before marketing approval can be given. This requirement includes maintenance of at least a minimum drug content during the expected shelf-life of the formulated product, while the unopened package is stored in a specified temperature and humidity environment. Where the drug is particularly sensitive to moisture, sometimes the packaging will incorporate a desiccant component to absorb moisture entering through the packaging materials and/or during repeated brief openings of the package.
There have been some approaches developed for reducing the effects of moisture on sensitive drugs. Sometimes the drug substance can be combined with a protective hydrophobic material, such as an oil or polymer. However, this frequently leads to other undesired effects, such as altering the drug solubility parameters, and can create difficulties in processing to manufacture a formulated product.
According to U.S. Pat. No. 7,807,715 it is necessary to enhance the chemical stability of fesoterodine and its salts in formulations, and this can be accomplished by granulating a mixture of the drug and a stabilizer selected from the group consisting of sorbitol, xylitol, polydextrose, isomalt, dextrose, and combinations thereof. The granulate is combined with excipient materials and compressed into tablet products. This patent, in its examples, teaches that mannitol, maltitol, and lactose act to increase the degradation of fesoterodine hydrogen fumarate, during storage of their granulates under various temperature and humidity conditions, so would not be desirable in granulation mixtures.
The drug fesoterodine fumarate is the active ingredient in a product being sold as TOVIAZ® tablets to treat urinary incontinence and frequency problems. Inactive ingredients are glyceryl behenate, hypromellose, indigo carmine aluminum lake, lactose monohydrate, soya lecithin, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and xylitol. The xylitol apparently is used as a drug stabilizer in the TOVIAZ product.
International Patent Application Publication No. WO 2012/098499 describes stabilizing fesoterodine fumarate by forming a molecular dispersion of the drug with an alkyl hydroxyalkylcellulose ether, a hydroxyalkylcellulose ether, an ester of either, or a mixture of any two or more thereof. The dispersion is said to not contain the drug in its crystalline or amorphous form, but has suitable stability.
European Patent Application Publication No. 2 508 173 describes stabilizing fesoterodine, or a salt or solvate thereof, by granulating with sucrose, polyethylene glycol, cyclodextrin, maltodextrin, or combinations thereof.
Considering all of these teachings, it becomes apparent that predicting the stability of a drug, when it is to be combined with various excipient substances, is not possible. Considerable effort is required to find suitable combinations that will deliver a moisture-sensitive drug in a desired, reproducible manner, facilitate pharmaceutical dosage form preparation, and provide the required drug stability during manufacturing, storage, and use.